The Influence of the Cholesterol Level in Cells on Endovanilloid Cytotoxicity
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HEMISTRY, BIOPHYSICS, AND MOLECULAR BIOLOGY
The Influence of the Cholesterol Level in Cells on Endovanilloid Cytotoxicity M. G. Akimova,*, P. V. Dudinaa, A. M. Gamisoniaa, N. M. Gretskayaa, G. N. Zinchenkoa, C. C. Mandalb, and V. V. Bezuglova Presented by Academician N.F. Myasoyedov Received March 11, 2020; revised March 19, 2020; accepted March 19, 2020
Abstract—The influence of the cellular cholesterol content on the cytotoxicity of endovanilloids acyldopamines was studied in MDA-MB-231 and MCF 10A cells. The activity of acyldopamines depends on the cellular cholesterol content, and a decrease in cholesterol content increases the cytotoxicity of acyldopamines. Keywords: acyldopamine cytotoxicity, endovanilloids, cholesterol, arachidonoyl dopamine, endocannabinoids DOI: 10.1134/S1607672920040018
Endovanilloids are a family of biologically active lipids, modulators of the nervous and immune systems. Their typical representatives are N-acyldopamines (NADA), containing long-chain saturated and unsaturated fatty acid residues. The main endovanilloid receptors are two classic cannabinoid receptors CB1 and CB2, the vanilloid receptor TRPV1, and the nonclassical cannabinoid receptor GPR55. The functioning of most of these receptors (except for CB2) depends on the integrity of lipid rafts. CB1 and GPR55 are present in rafts, and their activity decreases with the destruction of the latter [1]. TRPV1 activity also depends on lipid rafts, but only for some agonists [3]. We assumed that the activity of endovanilloids should be negatively correlated with the cholesterol content in cells. The aim of this work was to test the effect of cholesterol on the cytotoxicity of acyldopamines. Acyldopamines are known to induce apoptosis of cells by activating CB1, GPR55, or TRPV1 receptors on the plasma membrane [5–7]. Therefore, the induction of cell death was chosen as a detectable parameter. Human breast cancer cell lines MCF 10A (non-tumorigenic) and MDA-MB-231 (highly metastatic) were used as a model as lines with a potentially different state of the cholesterol metabolism system [8]. In this study, we tested dopamine amides of araa Shemyakin–Ovchinnikov Institute of Bioorganic Chemistry,
Moscow, Russia of Life Sciences, Central University of Rajasthan, NH 8, Bandarsindri, Kishangarh, Ajmer-305817, Rajasthan *e-mail:[email protected], [email protected] b School
chidonic (AA-DA), oleic (Ol-DA), and docosahexaenoic (DHA-DA) acids. The studied acyldopamines were synthesized according to the procedures developed previously [2]. The products were purified by column chromatography. The purity of the final product was evaluated using a reverse-phase HPLC microcolumn, and its structure was confirmed by 1H-NMR and ESI mass spectrometry. The purity of all compounds used in the experiments was at least 97%. MDA-MB-231 (ATCC HTB-26) and MCF 10A (ATCC CRL-10317) cells were cultured in DMEM supplemented with 4 mM L-glutamine, 10% fetal bovine serum, 100 units/mL penicillin, 100 μg/mL streptomycin, and 2.5 μg/mL amphotericin B at 37°C and
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